Nicotine exhausts CD8⁺ T cells against tumor cells through increasing miR-629-5p to repress IL2RB-mediated granzyme B expression

The mechanism exhausting CD8⁺ T cells is not completely clear against tumors. Literature has demonstrated that cigarette smoking disables the immunological activity, so we propose nicotine is able to exhaust CD8⁺ T cells. The CD8⁺ T cells from healthy volunteers with and without cigarette smoking and the capacity of CD8⁺ T cells against tumor cells were investigated. RNAseq was used to investigate the gene profiling expression in CD8⁺ T cells. Meanwhile, small RNAseq was also used to search novel microRNAs involved in the exhaustion of CD8⁺ T cells. The effect of nicotine exhausting CD8⁺ T cells was investigated in vitro and in the humanized tumor xenografts in vivo. We found that CD8⁺ T cells were able to reduce cell viability in lung cancer HCC827 and A549 cells, that secreted granzyme B, but CD8⁺ T cells from the healthy cigarette smokers lost anti-HCC827 effect. Moreover, nicotine suppressed the anti-HCC827 effect of CD8⁺ T cells. RNAseq revealed lower levels of IL2RB and GZMB in the exhausted CD8⁺ T cells. We identified that miR-629-5p was increased by nicotine, that targeted IL2RB. Transfection of miR-629-5p mimic reduced IL2RB and GZMB levels. We further validated that nicotine reduced granzyme B levels using a nuclear imaging technique, and demonstrated that nicotine exhausted peripheral blood mononuclear cells against HCC827 growth in the humanized tumor xenografts. This study demonstrated that nicotine exhausted CD8⁺ T cells against HCC827 cells through increasing miR-629-5p to suppress IL2RB.